Flow and microscopic heterogeneity of flow are believed to be a main determinants of how efficient the delivery of nutrients and pharmaceuticals to tissue takes place. Especially in diseases where delivery of nutrients such as e.g. oxygen is compromised by flow reduction, determination of flow heterogeneity is therefore crucial to assess the severity of the disease. Such diseases include acute cerebral ischemia, a frequent cause of death and the major cause of adult neurological disability in the Western world.
So far, the measurement of flow heterogeneity has been limited to the study to superficial vessels in the cortex of anaesthetised animals by high-speed intravital microscopy. There are no pre-existing tools that allow determination flow heterogeneity in deeper structures, or on humans as part of non-invasive, routine diagnostic procedures.
The study of the delivery of nutrients to the tissue is currently done by Positron Emission Tomography (PET). Due to the costs and lack of general availability of this technique, these studies can, however, not be performed in general patient management.
A major limiting factor in the development of new drugs in many diseases is the cost of preclinical and clinical trials to determine beneficial effects of new agents. In acute stroke, this is typically done by comparing long-term neurological scores of hundreds of treated and untreated patients. The costs of this work, as well as the total number of patients available, therefore limits the rate at which novel drugs become available for common use. There exists therefore an urgent need for techniques that in individual patients predict the progression of a disease or condition and may be used for monitoring of said progression, so that the progression for the individual patient can be assessed whereby e.g. the efficacy of a drug or a substance can be evaluated in details from a much more limited number of patients. Such techniques are not currently available.
With regards to determining tissue flow, most quantitative techniques utilise tomographic images of the distribution of radionucleides combined with invasive blood sampling. With the spatial resolution of some tomographic imaging techniques, the dimensions of vessels are too small to accurately determine arterial tracer concentration levels non-invasively. Instead, image elements containing partly tissue, partly blood vessels must be used in order to characterise the mere shape of the arterial input curve to the tissue. In such cases, absolute values of flow and volume cannot be found, and therefore a normalisation routine allowing (i) comparison of serial measurements in a single subject, (ii) comparison among subjects and (iii) absolute quantification the case of susceptibility MRI of the brain is necessary as described below.
The present invention describes and validates a new, non-invasive method that allows assessment of flow heterogeneity on generally available tomographic equipment (Magnetic Resonance (MR), Computed Tomography (CT), PET). Furthermore, the technique allows indirect assessment of metabolic parameters.
Finally, the technique has high predictive power in terms of disease progression in cerebral diseases such as ischemia, thereby providing the means for rapid assessment of the efficacy of novel therapies.